Rare coding variants in ten genes confer substantial risk for schizophrenia
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Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature |
| Vol/bind | 604 |
| Udgave nummer | 7906 |
| Sider (fra-til) | 509-516 |
| Antal sider | 8 |
| ISSN | 0028-0836 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
M.J.D. is a founder of Maze Therapeutics and Neumora Therapeutics. B.M.N. is a member of the scientific advisory board at Deep Genomics and Neumora Therapeutics, a member of the scientific advisory committee at Milken and a consultant for Camp4 Therapeutics, Merck and Biogen. A.P. is a member of the genomics advisory board at AstraZeneca. M.C.O., M.J.O. and J.T.W. are supported by a collaborative research grant from Takeda Pharmaceuticals. E.A.S. is currently an employee of the Regeneron Genetics Center. D.S.P. was an employee of Genomics plc; all analyses reported in this paper were performed as part of his employment at Massachusetts General Hospital and the Broad Institute. The remaining authors declare no competing interests. In the past year, S.V.F. received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Akili, Genomind, Ironshore, KemPharm/Corium, Noven, Ondosis, Otsuka, Rhodes, Supernus, Takeda, Tris and Vallon. In previous years, S.V.F. received support from: Alcobra, Arbor, Aveksham, CogCubed, Eli Lilly, Enzymotec, Impact, Janssen, Lundbeck/Takeda, McNeil, NeuroLifeSciences, Neurovance, Novartis, Pfizer, Shire, and Sunovion. With his institution, S.V.F. has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. S.V.F. receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health; Oxford University Press: Schizophrenia: The Facts; and Elsevier: ADHD: Non-Pharmacologic Interventions, and is Program Director of www.adhdinadults.com .
Funding Information:
The research reported in this publication was supported by the National Institute of Mental Health (NIMH) and the National Human Genome Research Institute of the National Institutes of Health under award numbers U01 MH105641, U01 MH105578, U01 MH105666, U01 MH109539, R01 MH085548, R01 MH085521,?R01 MH124851 and U54 HG003067. We would also like to acknowledge support from K. Dauten and E. Dauten, the Stanley Family Foundation and the Dalio Foundation, which has enabled us to rapidly expand our data generation collections with the goal of moving towards better treatments for schizophrenia and other psychiatric disorders. Further, we wish to acknowledge all of the research participants in the BRIDGES cohort, which?wassupported by NIMH under award numbers R01 MH094145 (M.B. and R.M.M., PIs) and U01 MH105653 (M.B., PI). The collection and storage of cases and controls from the Centre for Addiction and Mental Health (CAMH) in Toronto and from the Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King?s College London, in London was supported by funding from GlaxoSmithKline. CAMH was supported by the Canadian Institutes of Health Research (MOP-172013, J.?B. Vincent, PI, CAMH). IoPPN was supported by funding from the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and the Maudsley NHS Foundation Trust and by King?s College London. The views expressed are those of the author(s) and not necessarily those of the UK NHS, the NIHR or the UK Department of Health. Case and control collection was supported by the Heinz C. Prechter Bipolar Research Fund at the University of Michigan Depression Center to M.G. McInnis. Data and biomaterials were collected for the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a multi-centre, longitudinal project selected from responses to RFP NIMH-98-DS-0001, ?Treatment for Bipolar Disorder?, which was led by G. Sachs and coordinated by Massachusetts General Hospital in Boston, with support from 2N01 MH080001-001. The Genomic Psychiatric Cohort (GPC) was supported by NIMH (U01 MH105641 (C.N.P., PI), R01 MH085548 (C.N.P. and M.T.P., PIs) and R01 MH104964 (C.N.P. and M.T.P., PIs). The MCTFR study was supported through grants from the National Institutes of Health under numbers DA037904, DA024417, DA036216, DA05147, AA09367, DA024417, HG007022 and HL117626. The work at Cardiff University was supported by Medical Research Council Centre grant no. MR/L010305/1 and programme grant mo. G0800509.?We would like to acknowledge the?Pritzker Neuropsychiatric Disorders Research?Consortium?for funding sample collection efforts. The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724, and R248-2017-2003) and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation.?A.P. was supported by Academy of Finland Centre of Excellence in Complex Disease Genetics (grant no. 312074, 336824).S.V.F.?is supported by the European Union?s Horizon 2020 research and innovation programme under grant agreement no. 667302 and 965381; NIMH grants U01MH109536-01, U01AR076092-01A1, R0MH116037 and 5R01AG06495502; Oregon Health and Science University, Otsuka Pharmaceuticals and Supernus Pharmaceutical Company. T.S. was supported by a?NARSAD Young Investigator Award from the Brain and Behavior Research Foundation.
Funding Information:
We would like to thank the patients and families who participated in our studies during the past two decades, without whom our research and findings would not be possible. The research reported in this publication was supported by the National Institute of Mental Health (NIMH) and the National Human Genome Research Institute of the National Institutes of Health under award numbers U01 MH105641, U01 MH105578, U01 MH105666, U01 MH109539, R01 MH085548, R01 MH085521, R01 MH124851 and U54 HG003067. We would also like to acknowledge support from K. Dauten and E. Dauten, the Stanley Family Foundation and the Dalio Foundation, which has enabled us to rapidly expand our data generation collections with the goal of moving towards better treatments for schizophrenia and other psychiatric disorders. Further, we wish to acknowledge all of the research participants in the BRIDGES cohort, which wassupported by NIMH under award numbers R01 MH094145 (M.B. and R.M.M., PIs) and U01 MH105653 (M.B., PI). The collection and storage of cases and controls from the Centre for Addiction and Mental Health (CAMH) in Toronto and from the Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, in London was supported by funding from GlaxoSmithKline. CAMH was supported by the Canadian Institutes of Health Research (MOP-172013, J. B. Vincent, PI, CAMH). IoPPN was supported by funding from the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and the Maudsley NHS Foundation Trust and by King’s College London. The views expressed are those of the author(s) and not necessarily those of the UK NHS, the NIHR or the UK Department of Health. Case and control collection was supported by the Heinz C. Prechter Bipolar Research Fund at the University of Michigan Depression Center to M.G. McInnis. Data and biomaterials were collected for the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a multi-centre, longitudinal project selected from responses to RFP NIMH-98-DS-0001, ‘Treatment for Bipolar Disorder’, which was led by G. Sachs and coordinated by Massachusetts General Hospital in Boston, with support from 2N01 MH080001-001. The Genomic Psychiatric Cohort (GPC) was supported by NIMH (U01 MH105641 (C.N.P., PI), R01 MH085548 (C.N.P. and M.T.P., PIs) and R01 MH104964 (C.N.P. and M.T.P., PIs). The MCTFR study was supported through grants from the National Institutes of Health under numbers DA037904, DA024417, DA036216, DA05147, AA09367, DA024417, HG007022 and HL117626. The work at Cardiff University was supported by Medical Research Council Centre grant no. MR/L010305/1 and programme grant mo. G0800509. We would like to acknowledge the Pritzker Neuropsychiatric Disorders Research Consortium for funding sample collection efforts. The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724, and R248-2017-2003) and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. A.P. was supported by Academy of Finland Centre of Excellence in Complex Disease Genetics (grant no. 312074, 336824).S.V.F. is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 667302 and 965381; NIMH grants U01MH109536-01, U01AR076092-01A1, R0MH116037 and 5R01AG06495502; Oregon Health and Science University, Otsuka Pharmaceuticals and Supernus Pharmaceutical Company. T.S. was supported by a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
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